cAMP, a nearly universal signaling molecule, is synthesized from ATP by a broad family of adenylyl cyclases (AC). In mammals, there are two types of AC. One form spans the membrane and is encoded by a gene family consisting of nine related transmembrane ACs (tmAC). These are regulated by G proteins and other second messengers. The P.I. has recently identified a second type of mammalian AC, soluble AC (sAC) that is insensitive to the known modulators of tmACs and does not possess membrane spanning domains. tmAC and sAC appear to mediate opposite effects on cellular proliferation and are differentially modulated by pharmacological agents. sAC activity is directly regulated by bicarbonate ions. Since sAC is preferentially expressed in male germ cells and is the only known bicarbonate stimulated adenylyl cyclase in mammals, the investigators propose that it is an excellent candidate to play roles in aspects of sperm motility, capacitiation and the acrosome reaction. The proposed studies will determine the regulatory and enzymological profile of sAC and use pharmacological and genetic approaches to test the role of sAC in reproductive function. Long term plans include developing sAC as a potential target for pharmacological therapeutics affecting fertility.